Pathology of Calcific Uremic Arteriolopathy

#NephJC Chat

Tuesday August 20, 2019 9 pm Eastern Daylight Time

Wednesday August 21, 2019 9 pm British Summer Time, 1 pm Pacific Daylight Time

Wednesday August 21, 2019 9 pm India Standard Time

 This will be a joint session with the Dermatology Journal Club

JAMA Dermatol. 2019;155(7):789-796. doi:10.1001/jamadermatol.2019.0381

Localization, Morphologic Features, and Chemical Composition of Calciphylaxis-Related Skin Deposits in Patients With Calcific Uremic Arteriolopathy.

Hester Colboc, MD; Philippe Moguelet, MD; Dominique Bazin, MD; Priscille Carvalho, MD; Anne-Sophie Dillies, MD; Guillaume Chaby, MD; Hervé Maillard, MD; Diane Kottler, MD; Elisa Goujon, MD; Christine Jurus, MD; Marine Panaye, MD; Vincent Frochot, MD; Emmanuel Letavernier, MD, PhD; Michel Daudon, MD; Ivan Lucas, MD; Raphaël Weil, MD; Philippe Courville, MD; Jean-Benoit Monfort, MD; François Chasset, MD; Patricia Senet, MD; for the Groupe Angio-Dermatologie of the French Society of Dermatology.

PMID: 31116362 Full Text at JAMA Dermatology


Uremic calciphylaxis, also called calcific uremic arteriolopathy (CUA), is a debilitating condition with ischemic and/or necrotic skin lesions seen predominantly in end-stage kidney disease patients receiving dialysis. Historically, the gold-standard for diagnosis has been a deep skin biopsy. However, it is widely believed that calciphylaxis can koebnerize after mild skin trauma and the very procedure of obtaining a kidney biopsy may increase the risk of new ulceration, bleeding, infection, and exacerbate the already high morbidity and mortality. In an accompanying case report (summarized here), the authors describe the use of ultrasound-guided percutaneous core needle biopsy to obtain tissue for histological diagnosis, which could potentially bypass this risk as it avoids incisions of the dermis and epidermis.

The means to obtaining tissue for diagnosis notwithstanding, controversy exists as to the precise pathogenetic mechanism and specificity of the histological findings to calciphylaxis. In a previous blinded study, the authors compared histologic features of skin biopsy specimens obtained from patients with suspected calciphylaxis with specimens of healthy viable skin tissue obtained from patients on dialysis but without clinical manifestations of calciphylaxis who had undergone lower-extremity amputations for chronic peripheral vascular disease. Interestingly, they found that many of the features thought to be pathognomonic for calciphylaxis were present in both cohorts. Specifically, abnormalities in small arteries or arterioles were present in 35% of amputation specimens and 55% of skin biopsies. Thrombosis, but not calcification, was significantly more prevalent in skin biopsy specimens of patients with calciphylaxis.

Determination of chemical composition determination and description of the skin calcifications through physicochemical techniques could contribute to understanding pathogenesis of uremic calciphylaxis, leading to more appropriate and specific treatments. The aims of this study were to:

  1. Precisely determine the localization, morphologic features, and chemical composition of calcifications in the skin of patients with CUA

  2. Examine whether any association could be established between their microscopy findings and clinical characteristics.

The Study


Observational group: n = 36. Retrospective study of consecutive adults diagnosed with CUA in 7 French hospitals between January 1, 2006, and January 1, 2017. They were classified into 2 clinical subgroups, distal or proximal CUA based on the localization of skin lesions.

Controls: n = 10. Five skin samples from patients with arteriolosclerosis and five control samples from the negative margins of skin carcinoma resections served as controls.

Histopathologic analyses: Skin biopsy samples were sent to a centralized pathology laboratory. Each sample was examined with:

  1. Hematoxylin-eosin-saffron staining

  2. von Kossa staining

  3. Low-e microscope slides

  4. Field emission scanning electron microscopy (FE-SEM)

  5. μ Fourier transform infrared (FT-IR) spectroscopy

  6. Raman spectroscopy

Statistical Analysis: Data were expressed as median (range) or number (%). Fisher exact or χ2 tests were used to compare qualitative variables; Wilcoxon rank sum or Mann-Whitney tests were used to compare paired variables; and Mann-Whitney tests were used to compare non-paired or non–normally distributed variables.


CUA biopsy specimens were characterized by calcifications in small and medium-sized vessels that were composed exclusively of calcium-phosphate-apatite and showed:

  1. Circumferential deposition

  2. Intimal and medial deposition

  3. Interstitial deposits

On the other hand, the control biopsy specimens showed classic Mönckeberg medial calcifications that were never circumferential and no interstitial localization was observed.

Screenshot 2019-08-19 21.55.59.png


Skin deposits in patients with CUA or arteriolosclerosis were always composed of calcium–phosphate apatite, but their different localizations in the vessel walls could indicate different pathogenetic mechanisms. Arteriolosclerotic vessel walls are thickened, with medial hypertrophy, suggestive of slowly progressive thickening and degeneration of the arteriolar wall with secondary calcium–phosphate apatite accumulation. Circumferential CUA vascular deposits were located mostly in the intima of otherwise normal-appearing vessels, suggesting a faster and global process, with primary calcium deposition. Limitations of the study are its small sample size and retrospective nature of the study.

Summary and Future Directions

The multitude of diagnostic tools used in this study provide a better understanding of the morphologic, ultrastructural, and chemical characteristics of CUA. These deposits are initially vascular and develop rapidly in normal vessel walls, and are characterized by circumferential vascular and interstitial deposits. Although the chemical compositions of the calcifications were similar in CUA and arteriolosclerosis (calcium-phosphate apatite), the vessels’ appearances and deposit localizations differed, suggesting different pathogenetic mechanisms.

Such observations allow us to focus our research on particular pathophysiological pathways that could be key in the development of effective treatments. The study findings that CUA vascular calcifications were always circumferential suggests that therapeutic strategies with vasodilators might be less relevant than those using calcium solubilizing drugs. Therefore, drugs that act on calcium– phosphate precipitation, such as sodium thiosulfate, bisphosphonates, and vitamin K supplements, would seem to be more appropriate and a rational approach for future therapeutic studies on CUA.

Summary by Vandana Dua Niyyar, MD,

Nephrologist, Emory University, Atlanta Georgia

NSMC Intern, Class of 2019